An Overview of Solid Form Screening During Drug Development
Ann NewmanSeventh Street Development Group
PO Box 526, Lafayette, IN 47902765-650-4462
PPXRD-10 May 18, 2011 ©2011 Seventh Street Development Group
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Definitions
• Polymorph– FDA: crystalline and amorphous forms as well as solvated
and hydrated forms– Purists: crystalline forms with the same molecular
composition (for example two anhydrous forms can be polymorphs, or two monohydrates can be polymorphs, but an anhydrate and a monohydrate can not be polymorphs)
– How polymorph is used in journal articles and regulatory documents is important in understanding what is being said
• Solid form– Alternative to include all solid materials
• Polymorphs, solvates, hydrates, amorphous, salts, cocrystals, amorphous dispersions
FDA definition: http://www.fda.gov/CDER/GUIDANCE/7590fnl.htm#_Toc167002781 2
Solid FormsN
eutr
al
Classes of multicomponent molecular crystals
2. Hydrate/solvate1. Homomeric 4. Cocrystal hydrate
6. Salt hydrate/solvate
-
-
-
-
-
-
-
-
+
+
+
+
+
+
+
+
-
-
-
-
-
-
-
-
+
+
+
+
+
+
+
+
7. Salt cocrystal
-
+-
+
-
+-
+
-
+-
+
-
+-
+
-
+-
+
-
+-
+
8. Salt hydrate cocrystal
+-
+-
+-
+-
+-
+-
+-
+-
+-
+-
+-
+-
= API = water/
solvent
3. Cocrystal
= neutralguest
Ch
arge
d
5. Salt
--
---
-
+
+
+
+
++
--
---
-
+
+
+
+
++
+ = counterion
Polymorphs
3
Amorphous• Amorphous
– No long range order– Do possess short range order– Less physically and chemically
stable than crystalline materials– Higher dissolution than
crystalline materials
Harmon et al. AAPS Newsmagazine, 2009, Sept, 14-20
• Amorphous solid dispersions– Amorphous drug with polymer– Polymer stabilizes amorphous
drug – Results in better stability and
higher dissolution
amorphous
crystalline
XRPD
4
Form Characterization
•XRPD is front line technique to determine
– Crystalline vsamorphous
– Crystalline form– Changes in amorphous
materials
• Once new patterns are found other techniques can be used to determine– Solvation state– Stoichiometry– Possible mixtures– Etc.
5Stanton et al. J. Pharm Sci, 2010, 99, 3769-3778; Kennedy et al, Mol Pharm, 2008, 5, 981-993.
dispersion
amorphous free base
cocrystal
crystalline free base
crystalline free base
Why We Screen
25
220
Single Form
Multiple Forms
89% of compounds screened exhibited multiple forms (based on 245 screens) includes 10 steroids, 7 peptide-based
structures, 5 cephalosporins, 4 organometallics, 2 macrolideantibiotics
1 has 281 has 341 has 87
Stahly. Cryst. Growth Des, 2007, 7, 1007-1026
Form Screening vs Selection
• Screening– Find possible forms under various conditions– Search for seeds/forms, not a search for a process
• Selection– Determine which form has the best properties for
development
• Screen and selection are sometimes considered the same function– Not all forms found in a screen will be relevant when
choosing a lead candidate (example- solvates)– However, knowing the possible forms will help in
developing robust processes (API and drug product)
7
Screening and Selection
XRPD, DSC, TG, etc
Solvent and nonsolvent conditions
Usually one technique used (XRPD, Raman)
Group data to determine possible forms
Collect specific data (solvent content, stoichiometry)
Scale-up of select materials may be needed
XRPD, DSC, TG, moisture uptake, solubility, etc
Material with best properties
Characterize starting material
Generate samples
Analyze samples
Data analysis
Characterize materials
Select form
Scale-up
Scre
en
ing
Sele
ctio
n
Preliminary characterization
8
When to Screen
• Different screens can be performed at various stages of development
• Should have a good idea of form by end of Phase II meeting
preliminary stable focused/solid form comprehensive
Process Development
Clinical Trials
Drug Product Manufacture
API Manufacture
Formulation
Process Development
Preformulation
Synthesis
YearsDiscovery Launch
9
Screening Strategy
Carry out a polymorph screen
Carry out a salt screen (if applicable)
Carry out a cocrystal screen
Carry out an amorphous dispersion screen
Characterize material as received
Carry out a polymorph
screen on new salts
and cocrystalsPatent new forms
Evaluate the need for
additional screening
Carry out additional
studies if necessary 10
Earl
y D
evel
op
men
t
Evaluate alternative formulation strategies
using new forms
Patent new formulationsLate
Dev
elo
pm
ent
Manual Screens
• Salts, cocrystals, polymorphs, dispersions, amorphous• Samples produced individually• Solvent or solid methods used• Solvent methods
– Vials• Glass, silanized glass, acid or base washed, or polymer vials can be
used• Check stability of plastic vials with various solvents
– Capillaries, templates (polymers, gold, etc)
• Solid methods– Temperature or RH equilibration– Grinding, compression, sublimation– Cool from melt
11
XRPD Sample Holders
top fill back fill
capillary
rotation
wire loop
variable temperatureair tight
transmission12
zero background
• Large variety of sample holders available
• Can be specific to instrument or autosampler
• Need to maintain sample in random orientation
• Select a holder to accommodate the amount of sample produced
High Throughput Screens
Screening– Usually done in an array with wells,
tubes, or vials– Limited to solvent based methods– Limited crystallization conditions– Can generate large numbers of
samples
• Analysis – XRPD instrument needs to be
configured for plate– Issues with plate screens
– Small sample size– Solid not always on bottom of
vessel
XRPD
Storey et al. CrystallographyRev. 2004, 10, 45-56 13
EP 1 467 205 A1
Standard transmission
HT Transmission
XRPD Analysis
• Small sample size• Possible poor
signal to noise ratio
• Broad peaks with variable shapes
• Strong background
• Preferred orientation
14Wyttenback et al. Pharm Res. 2007, 24, 888-898
Carbamazepine screen
Issues with plate screens
Analysis
Sample AnalysisXRPD, IR, Raman
Data
Data AnalysisStorey et al. Crystallography Rev. 2004, 10, 45-56
plate
A
F
C
D
B
E
dendogram
metric multidimensional plot
XRPD
Microscopy (IR, Raman, optical)
Planning a screen
Variables to consider during crystallization/screening
Morrissette et al. Adv. Drug Delivery Rev. 2004, 56, 275-300
Order of addition
16
Planning a Screen
17Adapted from Anderton. Amer. Pharm. Rev. 2007, 10, 34-40
Salt Screening Strategy
Early salt screens
– Can be based on BCS
– Not as crucial for BCS class 1 materials
– More important for classes 2 and 4
BCS 1?
Soluble Salt?
Select Salt?
Free/Salt FormAnimal PK
Polymorph Screening
Free FormAnimal PK
Polymorph Screening
Polymorph Screening
Salt Animal PK
Salt Screening
yes
no
no
yes
Ku. Amer Pharm Rev. 2010, 13, 22-30
yes
Soluble salt defined as enabling human dose soluble in 250 mL water
18
Salt Development
• Requirements and selection process for each compound will be unique
• Variables that need to be considered when developing salts– solubility targeted– acceptable final form– dissolution– solubility of free compound– stability of free compound– melting point– dosage form to be developed– route of administration– loading in dosage form– amount of material available– previous experience with counterions– toxicology of counterions– etc
Properties related to form
Properties related to development
19
Clchloride
Brbromide
sulfate
nitrate
phosphate
SO4 HSO4
NO3
H2PO4HPO4
mesylate
esylate
isethionate
tosylate
napsylate
besylate
CH3SO3
SO3
SO3H3C
H3C SO3
SO3
HO
bicarbonate HCO3
SO3
citrate
lactate
malate
tartrate
stearate
HO2C CO2
HO CO2H
H3C CO2
OH
HO2C
OH
CO2
HO2CCO2
OH
OH
CH3(CH2)16CO2
succinate
glycolate
HO2CCO2
HO CO2
hexanoate
octanoate
decanoate
oleate
CH3(CH2)4CO2
CH3(CH2)6CO2
CH3(CH2)8CO2
HC(H2C)7H3C CH(CH2)7CO2
acetate
propionate
maleate
benzoateCO2
CH3CO2
H3C CO2
HO2C CO2
salicylate
fumarate
CO2
HO2C
CO2
OH
pamoate
OH
CO2H
CH2
OH
CO2
glutamate
aspartate
HO2C CO2
NH2
HO2CCO2
NH2
Counterion Selection
Consider size and shape of counterion and API
anions
20
triethylamine
ethanolamine
triethanolamine
ethylenediamine
cholinelithium
meglumine
aluminum
lysine
histidine
procaine
benzathine
sodium
potassium
calcium
magnesium
zinc
argenine
Na+
K+
Ca++
Mg++
Li+
Zn++
Al+++
CO2H
HNN NH3
H2N NH
CO2H
NH2
NH2
H3N CO2H
NH2
(CH3CH2)3NH+
HOCH2CH2NH3+
(HOCH2CH2)3NH+
H2NCH2CH2NH3+
HOCH2CH2N(CH3)3+
HO
OH
OH
OH
OH H2N
CH3
H2N
O
O
N
CH3
CH3
H
NH
H2N
Counterion Selection
cations
Not limited to inorganic counterions
Counterion Selection
Frequency of counterion in marketed products can be considered
0
10
20
30
40
50
60
Fre
qe
ncy
%
Cations
0
10
20
30
40
50
Fre
qu
en
cy %
Anions
Newman et al. Chapter 14. Salt and Cocrystal Form Selection in Preclinical Development Handbook. Wiley-Interscience, Hoboken. 2008, 455-481.
22
Counterion Selection
Frequency in dosage form can also be evaluated– Will change over time
Paulekuhn et al. J Med Chem 2007, 50, 6665-667223
Counterion Selection
pKa difference of 2 between API and counterion– Generally accepted for salt formation
• Cocrystals possible if ignored
– pKa values can change significantly in different solvents– Based on solution chemistry
• Need to think about solubilities of solids
Black et al. J Pharm Sci 2007, 96, 1053-1068 24
Counterion Selection
Effect of Solvent on pKa
– 25 counterions used to make ephedrine slats
Black et al. J Pharm Sci 2007, 96, 1053-106825
Counterion Selection
• Toxicity
– Depends on molecule and daily dose
– Will be different for short term vs chronic dosing
– Toxic reaction products need to be considered
• Methyl and ethyl formate esters associated with formic acid under certain conditions
• Methyl methanesulfonate, a known mutagen, associated with methanesulfonic acid
– Usually an issue when methanol is used as solvent
26
Salt Formation
• Solvent methods– Evaporation– Cooling– Antisolvent addition– Sonic slurry– Capillaries
• Number of parameters to investigate– Solvent,
concentration/stoichiometry, cooling rates, evaporation rates
– Manual or automated crystallization
• Solubilities– API and counterion/guest need to
be soluble in same solvent or miscible solvents
• Try to get precipitation– reduce volume – cool solution– add anti-solvent (if known)– different ways of combining
compounds– different temperatures
• Evaporations can result in physical mixture of materials rather than salt, or other unknown forms of free compound
27
Salt Formation
• A variety of less traditional methods are also available– binary melt (cocrystal formation as well)
– grinding (cocrystal formation)/trituration
– salt exchange
– bubble gas (HCl, HBr) through solution
– vapor diffusion
– ion exchange resins
– phase solubility (solubility as a function of pH)
– precipitation of unwanted counterion first (ex. Silver salts used as counterion source and silver precipitated as silver iodide leaving desired anion)
• Try to get salts for evaluation or use process that is scaleable?
Newman and Stahly. Form Selection of Pharmaceutical Compounds in Handbook of Pharmaceutical Analysis. Marcel Dekkar: New York, 2002, 1-57 28
Salt Formation
• Different stoichiometries can be tried
– more than one site on free compound
– diacid counterion used (fumarate, malate, maleate, tartrate, etc)
• Control of stoichiometry may be an issue if pKa values are close
CO2
HO2C
HO2C
OH
CO2HO2C
CO2
OH
OH
HO2C CO2
30
Characterization
• API with two basic sites– similar pKa values
• HBr salt prepared with different molar ratios– Same XRPD pattern– Same elemental analysis– Different yields
• Favors formation of disalt
Element 1:1 HBr:API 2:1 HBr:API Expected Values for
Disalt
C 49.77 49.92 49.48
H 4.05 3.97 3.97
N 14.83 14.91 15.05
Br 28.86 29.20 28.63
poor yield good yield
1:1
2:1
Newman et al. Chapter 14. Salt and Cocrystal Form Selection in Preclinical Development Handbook. Wiley-Interscience, Hoboken. 2008, 455-481. 31
Characterization
X-ray Powder Diffraction (XRPD)Crystallinity
Crystalline form
Spectroscopy• Infrared (IR)• Raman• NMR
Thermal Methods•DSC (mDSC, HyperDSC)•Thermogravimetry (TG)•Hot Stage Microscopy
Moisture Sorption
InteractionsCrystalline form
Mapping/imaging
Melting point/TgForm changes
Volatile content
Water uptakeForm changes
Crystalline pattern
Interactions between drug and counterion
Stoichiometry
One meltIdentify additional
transitions
Low water uptake
Solubility, stability, formulation
Evaluation
• Solubility in water 0.1-10 mg/mL for solid oral dosage forms 10 mg/mL for parenterals
•pH of aqueous solution 3-10 for parenterals
•Melting point >100 °C
• Hygroscopicity Non-deliquescent at 60-75% RH
• Chemically and physically stable (excipient compatibility)• Dissolution rate• Crystal size, shape
Evaluation
Tier 1 Hygroscopicity
(7 salts)
Tier 2 Solubility/Crystal Changes
(4 salts)
Tier 3 Stability and Compatibility
(1 salt and alternate)
Sodium 180431-03
Calcium 180431-04
Zinc 180431-05
Magnesium 180431-06
Potassium 180431-07
Lysine 180431-08
Arginine 180431-09
Morris et al. Int. J. Pharmaceutics 1994, 105, 209
Salt Selection
Decision tree• General properties• Needs to be tailored to each
system
Continue crystallization attempts
Yes
No
Unacceptable
Yes
No
CrystallinityCan crystalline salts
be prepared?
HygroscopicityDoes the salt deliquesce
at high humidity?Solubility enhancement
If necessary
Yes
NoSolubilityDoes the salt have aqueous solubility?
Stability enhancement
If necessary
Yes
NoStabilityIs the salt physically stable
under accelerated conditions?
Yes
NoPolymorphismAre there multiple
polymorphs of the salt?Secondary
Candidates
Yes
NoControlCan the process be
controlled to produce desired form?
Final SaltCandidate
Final SaltCandidate
Crystallization
• Scale-up needs to be considered
• Ternary phase diagrams can be useful to determine concentrations
E: ephedrine S: salt L: liquidA: adipic acid
M: malic acid
Black et al. J Pharm Sci 2007, 96, 1053-1068
Salt Screening
• A variety of salts are available
– Salts, salt hydrates/solvates, salt cocrystals, salt cocrystalhydrates/solvates
• Salt screening can be used to find new salts
– Solvent methods most common
– Manual vs automated
• Characterization of salts needed
– Form, protonation
• Scale-up can be an issue
• Salts can significantly alter properties of API
– Melting point, solubility, stability, dissolution, bioavailability
• Salts can exhibit polymorphism- polymorph screen should be performed
Polymorph Screening
• Search for seeds, not a search for a process– Do not limit to Class III solvents– Do not limit to solvent experiments– Can gain information on crystallization process
(example- solvate formation, slurry expts)– Can always use the initial crystals as seeds for a
crystallization process
• Need to determine which forms are relevant to development – Anhydrates vs hydrates vs solvates – Initial goal is to find the most thermodynamically
stable form
• No screen can guarantee to find all forms
Sample Generation
• Solvent based methods can be employed based on solubility in various solvents– High solubility systems
• High concentrations can result in gels/oils
• Antisolvent additions, cooling experiments below supersaturation
– Low solubility systems• Want to increase solubility or allow time for conversion
• Slurry experiments, cooling crystallization from elevated temperature
• Start with amorphous material to increase solubility
• Can tailor crystallization experiments to increase success
Sample Generation
Polla et al., Int. J. Pharm. 2005, 301, 33-40
olanzapine
• Nonsolvent methods can be tailored based on other properties/data– Heating/desolvation
temperature based on TG loss
– Heating/melting temperature based on DSC, hot stage data
– Exposure to RH conditions based on water uptake data
LY334370 HCl
Reutzel-Edens et al. J. Pharm. Sci. 2003, 92, 1196-1205
Planning a Screen
Understand goal of screen and what information is needed
• For early screens want to know most stable form
• For later screens, may want additional information for processing or IP
Goal Screen Type Material
Determine propensity for polymorphism preliminary <0.5 g
Find thermodynamically stable form stable form 1-2 g
Confirm the selected form can be produced withGMP material
focused 1-2 g
Find the best form for development solid form selection 2-5 g
Widest experimental scope to find all possible forms comprehensive variable
Stahly. Crystal Growth Des. 2007, 7, 1007-1026
How Many Samples
Depends on – Goal of screen and information needed
– Amount of material available
– Information already available (stability, solubility, etc)
Goal Screen Type Material Number of Experiments
Determine propensity for polymorphism
preliminary <0.5 g tens
Find thermodynamically stable form stable form 1-2 g tens
Confirm the selected form can be produced with GMP material
focused 1-2 g tens
Find the best form for development solid form selection 2-5 g hundreds
Widest experimental scope to find all possible forms
comprehensive variable thousands
Stable Form Screen
Stable Form Screen– Targeted for early
development to find the most stable form
– Small amount of compound needed (100-250 mg)
– Slurry experiments used (solvent mediated polymorphic transformation)
– Material suspended in diverse group of solvents for two weeks
– Solubility estimated using gravimetric method
Miller et al. Pharm. Dev. Technol. 2005, 10, 291-297
MetastableForm
dissolution Stable Form
SupersaturatedSolution
nucleation
crystal growth
Stable Form Screen
Pfizer Compound A• Form I was initial form• Transformation to more stable Form II observed
– 6 out of 18 solvents in 2 days and 8 out 18 solvents in 2 weeks produced Form II– Dioxane solvate also found
Miller et al. Pharm. Dev. Technol. 2005, 10, 291-297
decompositionFastest tranfsormationat highest solubilities
HTS
High throughput screening (HTS)– Comparison of manual vs HTS
– Goal of screen was form diversity, not stable form
– 1500 experiments performed• 186 solids found after 7 days (13%
hit rate)
• After Raman clustering, 80 samples analyzed by XRPD
MK-996
Almarsson et al. Cryst Growth Des. 2003, 3, 927-933
HTS
• HTS screen found 18 forms– 13 new patterns
– 5 previously known forms
• Screen did not find 4 previously known forms– Forms B and C (unsolvated), F, H
– Form D was found in HTS. Original paper could not reproduce Form D after Form I was found.
• Form I originally chosen for development
Almarsson et al. Cryst Growth Des. 2003, 3, 927-933
a. Form reported in original paper: Jahansouz et al. Pharm
Dev. Technol. 1999,4,181-187
Polymorph Screens
• Need to understand the goal of the screen– most stable form, form diversity, change a specific
property
• A variety of screens are possible– Manual, high throughput, etc
• Can tailor crystallization experiments to the properties of the molecules– Solubility for solvent based methods– Characterization data for solid experiments
• Multiple screens may be warranted throughout development
47
Case StudyAMG 837• Treatment for type 2 diabetes• Initially isolated as lysine salt
– Poorly crystalline by XRPD– Hygroscopic above 65% RH– Difficult to scale up due to large volumes of solvent (>100 vol EtOH)
• Free acid investigated– Crystalline by XRPD– Poorly soluble (~0.5 mg/mL) and poor wettability– DSC showed low melting point of 80 C– Poor solution and solid-state stability– Benchtop polymorph screen conducted
• Higher melting forms not identified• Samples usually thick oils and difficult to crystallize
• Salt screen performed to identify crystalline form with acceptable characteristics for development
48Morrison et al. Org Proc Res Dev 2011, 15, 104-111
Case Study
• Ten counterions used• Crystallization included
– Evaporation, slurries, antisolventaddition
49
Counterion XRPD Results Priority Comment
L-Arginine --- ---
Calcium Amorphous Low Amorphous
Choline Crystalline High
Ethanolamine Crystalline Low No marketed oral drugs identified
L-Histidine --- ---
Magnesium Amorphous Low Amorphous
Meglumine --- ---
Potassium Amorphous Low Amorphous
Sodium Crystalline High
TRIS Crystalline Medium Marketed products identified, counterionnot employed for oral chronic use
Morrison et al. Org Proc Res Dev 2011, 15, 104-111
• Prioritized based on crystallization and information on counterions• Choline and sodium listed as high
priority• Counterion use in marketed products also
considered
Case Study
• Salt Screen
– Four crystalline hits identified
– Ethanolamine and TRIS were considered second tier
– Sodium had higher melting point than choline
– Sodium salt chosen
50Morrison et al. Org Proc Res Dev 2011, 15, 104-111
Case Study• Full polymorph screen of sodium salt performed
– Eight patterns observed
– Forms E and H showed highest crystallinity
51Morrison et al. Org Proc Res Dev 2011, 15, 104-111
Case Study
• Four forms examined in more detail
52
Form Eacetonitrilesolvate (8%)
Form Chemihydrate
ambient RH
Form Hunsolvated
heating
Form Gunsolvated
ambient RH
• Form C chosen for further investigation• Found most often in screen• Solubility >100 mg/mL• Successfully scaled up for use as GLP and GMP material
Morrison et al. Org Proc Res Dev 2011, 15, 104-111
Case Study
• Successfully scaled up for use as GLP and GMP material– Produced Form E solvate then desolvated to Form C– GMP more crystalline than GLP material
53Morrison et al. Org Proc Res Dev 2011, 15, 104-111
Case Study• Form C exhibited multiple thermal
transitions– Broad endo ~61 °C– Endos at ~ 151 and 182 °C– Exo ~ 186 °C– Major endo at 187 °C (melt of Form G)
54
• VT-XRPD performed• 120 °C
• Slight changes to form isomorphous dehydrate
• 165 °C• New form (Form I) which
melts at 182 °C and recrystallizes
• 183 °C• Form G which melts at 187 °C Morrison et al. Org Proc Res Dev 2011, 15, 104-111
Isomorphousdehydrate
Isomorphous dehydrate
Form I
Form I
Form G
Case Study
• Form C showed mix of properties– Low crystallinity– Complicated DSC profile– Hygroscopic– Good short term physical stability at 68% RH, 60 C/26% RH,
60 C/50% RH
• Form C suitable for Phase I clinical trials• Went back to original screen to find better candidate• Sodium salt used to produce a crystalline hemicalcium
salt• Polymorph screen of calcium salt performed
55
Case Study• Full polymorph screen conducted using both amorphous
and crystalline calcium salt• Five crystalline forms produced
56Morrison et al. Org Proc Res Dev 2011, 15, 104-111
Case Study• All forms contained solvent• Characterization showed that none of the forms exhibited a true melt
– Desolvation upon heating produced amorphous materials– Crystalline forms needed solvent to stabilize the crystal lattice
57
Form Results Comment
A methanol solvate solvate
B dihydrate candidate
C dihydrate candidate
D isopropanol solvate solvate
E pentahydrate Converted to Form C upon heating or exposure <55% RH
• Solubility used to determine thermodynamic stability of Forms B and C• Form B had lower solubility at 5, 21, and 40 °C• Form B was more stable form• Form B stable to small scale wet milling conditions to simulate wet
granulationMorrison et al. Org Proc Res Dev 2011, 15, 104-111
Case Study• Both Form B calcium salt and Form C sodium salt were
viable candidates
• A number of quality attributes were considered
• Calcium salt was recommended for product development
58Morrison et al. Org Proc Res Dev 2011, 15, 104-111
Case Study• Summary
– Initial salt screen performed due to unfavorable characteristics of free base• Low melt, poor stability, poor water solubility• Eleven counterions included in screen
– Most yielded amorphous materials– Others not preferred due to lack of chronic oral use data and safety implications– Sodium salt moved forward
– Second salt screen performed to improve properties – Calcium salts revisited based on crystallization of sodium salt– Polymorph screens performed on both sodium and calcium salts
– 8 forms found for sodium, 5 forms found for calcium
– Hemicalcium salt chosen for development based on properties
• More than one salt screen and more than one polymorph screen used to pick the best form during development
• Form matrix used for form selection
59Morrison et al. Org Proc Res Dev 2011, 15, 104-111
What Have We Learned
• X-ray powder diffraction is a key characterization technique for screening and selection studies
• Screening is different from selection
• Polymorph and salt screens – Are a search for seeds and should cover a wide crystallization space
including solvent and nonsolvent methods
– Can be tailored to the information needed for compound development
– Should use information already known on the compound
– Can be performed at various points during development
• One screen will likely not give you all the form information on a compound
• Finding and characterizing forms early will help– In choosing the best form for development
– To avoid processing conditions that could produce another form
60
ResourcesPolymorph Screening• Guillory. Chapter 5 in Polymorphism in
Pharmaceutical Solids, H. G. Brittain, Ed., Marcel Dekkar, New York 1997.
• Hilfiker et al. Chapter 11 in Polymorphism in the Pharmaceutical Industry, R. Hilfiker, Ed., Wiley-VCH, Weinheim 2006.
• Maiwald. Amer Pharm Rev. 2006, May/June, 95-99.
• O’Neill. Pharm. Technol. 2003, 44—56.• Aaltonen et al. Eur J Pharm Biopharm. 2009, 71,
23-37.• Grzesiak et al. J Pharm Sci. 2008, 97, 2130-2144
(polymers templates).• Alleso et al. J Pharm Sci, 2010, 99, 3711-3718
(processing stresses).• Cui et al. J Pharm Sci. 2007, 97, 2730-2743
hydrates).• Sistla et al Pharm Dev Technol. 2011, 16, 102-
109 (hydrates).• Campeta et al. J Pharm Sci 2010, 99, 3874-3886
(solvates).
Salt Screenig• Stahl and Wermuth. Handbook of
Pharmaceutical Salts. Wiley-VCH, Weinheim. 2002.
• Berge et al. J. Pharm. Sci. 1977, 66, 1–19.• Gould. Int. J. Pharm. 1986, 33, 201–217.• Bastin et al. Org Proc Res Dev. 2000, 4, 427-
435.• Veerbeck and Walker. Europ. J Pharm Sci.
2006, 28, 1-6.• Huang and Tong. Adv Drug Deliv Rev. 2004,
56, 321-334.• Tong and Whitesell. Pharm Dev Tech. 1998,
3, 215-233.• Morris et al. Int. J. Pharmaceutics 1994, 105,
209
61
Ann NewmanSeventh Street Development Group
www.seventhstreetdev.com